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November 27, 2013

Myriad Genetics Sues Invitae over BRCA Gene Testing and Invitae Sues Right Back

The latest company targeted by Myriad Genetics for offering a genetic diagnostic test encompassing the human BRCA 1 and BRCA 2 genes is Invitae Corp. located in San Francisco. Myriad sued Invitae on Monday in the District of Utah, Central Divisions (Case No. 2:13-CV-01049-EJF; complaint), and the next day Invitae filed its own lawsuit, seeking a declaratory judgment, in the Northern District of California (Case No. 3-13-cv-05495; complaint). Myriad's complaint is similar to Myriad's complaints against other defendants, and includes infringement allegations relating to its mutY homolog (MUTYH) test for hereditary colon cancer in addition to its BRCA gene patent-based claims. Once again, Myriad is joined by the University of Utah Research Foundation, the Trustees of the University of Pennsylvania, HSC Research and Development Limited Partnership, and Endorecherche Inc.

This Complaint alleges that:

On September 10, 2013, Defendant announced that it would "add BRCA1 and BRCA2 testing in future product releases." At the 2013 Annual Meeting of the Association for Molecular Pathology held in Phoenix, Arizona from November 12-16, 2013, Defendant announced that it would begin offering its BRCA1 and BRCA2 analysis as part of its cancer-testing menu during the week of November 18, 2013. Defendant added BRCA1 and BRCA2 gene testing into the offered panel testing services promoted on its website on November 19, 2013. On information and belief, Defendant offers full gene sequencing and deletion/duplication analyses for the BRCA 1, BRCA 2, and MUTYH genes as part of multiple hereditary cancer panels that test cancer susceptibility using next-generation sequencing technology.

This complaint is unlike several of Myriad's earlier complaints, insofar as Myriad is not asserting certain patents or claims that it has asserted in past complaints. These non-asserted patents and claims include:

Claim 6: A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1, wherein a germline alteration is detected by amplifying all or part of a BRCA1 gene in said sample using a set of primers specific for a wild-type BRCA1 gene to produce amplified BRCA1 nucleic acids and sequencing the amplified BRCA1 nucleic acids.

Claim 16: A pair of single-stranded DNA primers for determination of a nucleotide sequence of a BRCA1 gene by a polymerase chin reaction, the sequence of said primers being derived from human chromosome 17q, wherein the use of said primers in a polymerase chain reaction results in the synthesis of DNA having all or part of the sequence of the BRCA1 gene.

Claim 17: The pair of primers of claim 16 wherein said BRCA1 gene has the nucleotide sequence set forth in SEQ ID NO:1.

Claim 29. A pair of single-stranded DNA primers of at least 15 nucleotides in length for determination of the nucleotide sequence of a BRCA2 gene by a polymerase chain reaction, the sequence of said primers being isolated from human chromosome 13, wherein the use of said primers in a polymerase chain reaction results in the synthesis of DNA comprising all or at least 15 contiguous nucleotides of the BRCA2 gene.

Claim 30. The pair of primers of claim 29 wherein said BRCA2 gene has the nucleotide sequence set forth in SEQ ID NO:1.

Claim 2. A method of identifying individuals having a BRCA1 gene with a BRCA1 coding sequence not associated with breast or ovarian cancer comprising: a) amplifying a DNA fragment of an individual's BRCA1 coding sequence using an oligonucleotide primer which specifically hybridizes to sequences within the gene; b) sequencing said amplified fragment by dideoxy sequencing; c) repeating steps (a) and (b) until said individual's BRCA1 coding sequence is completely sequenced; d) comparing the sequence of said amplified DNA to the sequence of SEQ. ID. NO: 1; e) determining the presence or absence of each of the following polymorphic variations in said individual's BRCA1 coding sequence: AGC and ACT at position 2201, TTG and CTG at position 2430, CCG and CTG at position 2731, GAA and GGA at position 3232, AAA and AGA at position 3667, TCT and TCC at position 4427, and ACT and GGT at position 4956; f) determining any sequence differences between said individual's BRCA1 coding sequences and SEQ. ID. NO: 1 wherein the presence of any of the said polymorphic variations and the absence of a polymorphism outside of positions 2201, 2430, 2731, 3232, 3667, 4427, and 4956, is correlated with an absence of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA1 mutation in the BRCA1 coding sequence.

Claim 3. A method according to claim 2 wherein said oligonucleotide primer is labeled with a radiolabel, a fluorescent label, a bioluminescent label, a chemiluminescent label or an enzyme label.

Claim 4. A method of detecting an increased genetic susceptibility to breast and ovarian cancer in an individual resulting from the presence of a mutation in the BRCA1 coding sequence, comprising: a) amplifying a DNA fragment of an individual's BRCA1 coding sequence using an oligonucleotide primer which specifically hybridizes to sequences within the gene; b) sequencing said amplified fragment by dideoxy sequencing; c) repeating steps (a) and (b) until said individual's BRCA1 coding sequence is completely sequenced; d) comparing the sequence of said amplified DNA to the sequence of SEQ. ID. NO: 1; e) determining any sequence differences between said individual's BRCA1 coding sequences and SEQ. ID. NO: 1 to determine the presence or absence of polymorphisms in said individual's BRCA coding sequences wherein a polymorphism which is not any of the following: AGC or AGT at position 2201, TTG or CTG at position 2430, CCG or CTG at position 2731, GAA or GGA at position 3232, AAA or AGA at position 3667, TCT or TCC at position 4427, and AGT or GGT at position 4956; is correlated with the potential of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA1 mutation in the BRCA1 coding sequence.

Claim 2. A method of identifying individuals having a BRCA1 gene with a BRCA1 coding sequence not associated with ovarian or breast cancer disease, comprising: (a) amplifying a DNA fragment of an individual's BRCA1 coding sequence using an oligonucleotide primer which specifically hybridizes to sequences within the gene; (b) sequencing said amplified DNA fragment by dideoxy sequencing; (c) repeating steps (a) and (b) until said individual's BRCA1 coding sequence is completely sequenced; (d) comparing the sequence of said amplified DNA fragment to a BRCA1(omi) DNA sequence selected from the group consisting of: SEQ ID NO: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5; (e) determining the presence or absence of each of the following polymorphic variations in said individual's BRCA1 coding sequence: (i) C and T at position 2201, (ii) T and C at position 2430, (iii) C and T at position 2731, (iv) A and G at position 3232, (v) A and G at position 3667, (vi) T and C at position 4427, and (vii) A and G at position 4956; (f) determining any sequence differences between said individual's BRCA1 coding sequences and a BRCA1(omi) DNA sequence selected from the group consisting of: SEQ ID NO: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5, wherein the presence of said polymorphic variations and the absence of a variation outside of positions 2201, 2430, 2731, 3232, 3667, 4427 and 4956 is correlated with an absence of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA1 mutation in the BRCA1 coding sequence.

Claim 3. A method of identifying individuals having a BRCA1 gene with a BRCA1 coding sequence not associated with ovarian or breast cancer disease, comprising: (a) amplifying a DNA fragment of an individual's BRCA1 coding sequence using an oligonucleotide primer which specifically hybridizes to sequences within the gene; (b) sequencing said amplified DNA fragment by dideoxy sequencing; (c) repeating steps (a) and (b) until said individual's BRCA1 coding sequence is completely sequenced; (d) comparing the sequence of said amplified DNA fragment to a BRCA1(omi)) DNA sequence selected from the group consisting of: SEQ ID NO: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5; (e) determining the presence or absence of each of the following polymorphic variations in said individual's BRCA1 coding sequence: (i) C and T at position 2201, (ii) T and C at position 2430, (iii) C an d T at position 2731, (iv) A and G at position 3232, (v) A and G at position 3667, (vi) T and C at position 4427, and (vii) A and G at position 4956; and (f) determining any sequence differences between said individual's BRCA1 coding sequences and a BRCA1(omi) DNA sequence selected from the group consisting of: SEQ ID NO: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5, wherein the presence of said polymorphic variations and the absence of a variation outside of positions 2201, 2430, 2731, 3232, 3667, 4427 and 4956 is correlated with an absence of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA1 mutation in the BRCA1 coding sequence; wherein codon variations occur at the following frequencies, respectively, in a Caucasian population of individuals with no family history of breast or ovarian cancer: (i) at position 2201, C and T occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (ii) at position 2430, T and C occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (iii) at position 2731, C and T occur at frequencies from about 25 to about 35%, and from about 65 to about 75%, respectively; (iv) at position 3232, A and G occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (v) at position 3667, A and G occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (vi) at position 4427, T and C occur at frequencies from about 45 to about 55%, and from about 45 to about 55%, respectively; and (vii) at position 4956, A and G occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively.

Claim 4. A method according to claims 2 or 3, wherein said oligonucleotide primer is labeled with a radiolabel, a fluorescent label, a bioluminescent label, a chemiluminescent label, or an enzyme label.

Claim 5. A method of detecting an increased genetic susceptibility to breast and ovarian cancer in an individual resulting from the presence of a mutation in the BRCA1 coding sequence, comprising: (a) amplifying a DNA fragment of an individual's BRCA1 coding sequence using an oligonucleotide primer which specifically hybridizes to sequences within the gene; (b) sequencing said amplified DNA fragment by dideoxy sequencing; (c) repeating steps (a) and (b) until said individual's BRCA1 coding sequence is completely sequenced; (d) comparing the sequence of said amplified DNA fragment to a BRCA1(omi) DNA sequence selected from the group consisting of: SEQ ID NO: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5; (e) determining any sequence differences between said individual's BRCA1 coding sequences and a BRCA1(omi) DNA sequence selected from the group consisting of: SEQ. ID. NO.: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5 in order to determine the presence or absence of base changes in said individual's BRCA1 coding sequence wherein a base change which is not any one of the following: (i) C and T at position 2201, (ii) T and C at position 2430, (iii) C and T at position 2731, (iv) A and G at position 3232, (v) A and G at position 3667, (vi) T and C at position 4427, and (vii) A and G at position 4956, is correlated with the potential of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA1 mutation in the BRCA1 coding sequence.

Claim 6. A method of detecting an increased genetic susceptibility to breast and ovarian cancer in an individual resulting from the presence of a mutation in the BRCA1 coding sequence, comprising: (a) amplifying a DNA fragment of an individual's BRCA1 coding sequence using an oligonucleotide primer which specifically hybridizes to sequences within the gene; (b) sequencing said amplified DNA fragment by dideoxy sequencing; (c) repeating steps (a) and (b) until said individual's BRCA1 coding sequence is completely sequenced; (d) comparing the sequence of said amplified DNA fragment to a BRCA1(omi) DNA sequence selected from the group consisting of: SEQ ID NO: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5; (e) determining any sequence differences between said individual's BRCA1 coding sequences and a BRCA1(omi) DNA sequence selected from the group consisting of: SEQ ID NO: 1 together with SEQ ID NO: 3, SEQ ID NO: 1 together with SEQ ID NO: 5, SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 1 together with SEQ ID NO: 3 together with SEQ ID NO: 5, SEQ ID NO: 3 and SEQ ID NO: 5 in order to determine the presence or absence of base changes in said individual's BRCA1 coding sequence wherein a base change which is not any one of the following: (i) C and T at position 2201, (ii) T and C at position 2430, (iii) C and T at position 2731, (iv) A and G at position 3232, (v) A and G at position 3667, (vi) T and C at position 4427, and (vii) A and G at position 4956, is correlated with the potential of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA1 mutation in the BRCA1 coding sequence, wherein codon variations occur at the following frequencies, respectively, in a Caucasian population of individuals with no family history of breast or ovarian cancer: (i) at position 2201, C and T occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (ii) at position 2430, T and C occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (iii) at position 2731, C and T occur at frequencies from about 25 to about 35%, and from about 65 to about 75%, respectively; (iv) at position 3232, A and G occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (v) at position 3667, A and G occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively; (vi) at position 4427, T and C occur at frequencies from about 45 to about 55%, and from about 45 to about 55%, respectively; and (vii) at position 4956, A and G occur at frequencies from about 35 to about 45%, and from about 55 to about 65%, respectively.

Claim 7. A method according to claims 5 or 6, wherein said oligonucleotide primer is labeled with a radiolabel, a fluorescent label, a bioluminescent label, a chemiluminescent label, or an enzyme label.

Claim 73. A chip array having "n" elements for performing allele specific sequence-based techniques comprising: a solid phase chip and oligonucleotides having "n" different nucleotide sequences, wherein "n" is an integer greater than one, p1 wherein said oligonucleotides are bound to said solid phase chip in a manner which permits said oligonucleotides to effectively hybridize to complementary oligonucleotides or polynucleotides, wherein oligonucleotides having different nucleotide sequence are bound to said solid phase chip at different locations so that a particular location on said solid phase chip exclusively binds oligonucleotides having a specific nucleotide sequence, and wherein at least one oligonucleotide is an oligonucleotide that is an isolated nucleotide that hybridizes to either a normal or a mutant BRCA1 gene selected from the group consisting of: a first oligonucleotide for detecting a deletion of a nucleotide in intron 6 at nucleotide number 421-2 of a BRCA1 gene sequence, wherein said first oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 421-2 of the BRCA1 gene, a second oligonucleotide for detecting a deletion of two nucleotides at nucleotide number 815 of a BRCA1 gene sequence, wherein said second oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 815 of the BRCA1 gene, a third oligonucleotide for detecting an insertion of 10 nucleotides at nucleotide number 926 of a BRCA1 gene sequence, wherein said third oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 926 of the BRCA1 gene, a fourth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 1506 of a BRCA1 gene sequence, wherein said fourth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 1506 of the BRCA1 gene, a fifth oligonucleotide for detecting a mutation of one nucleotide at nucleotide number 2034 of a BRCA1 gene sequence, wherein said fifth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 2034 of the BRCA1 gene, a sixth oligonucleotide for detecting an amino acid change from serine to a stop codon at codon 770 of a BRCA1 gene sequence, wherein said sixth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 2428 of the BRCA1 gene, a seventh oligonucleotide for detecting an amino acid change from tryptophan to a stop codon at codon 1508 of a BRCA1 gene sequence, wherein said seventh oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 4643 of the BRCA1 gene, an eighth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5053 of a BRCA1 gene sequence, wherein said eighth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5053 of the BRCA1 gene, an ninth oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5210 of a BRCA1 gene sequence, wherein said ninth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5210 of the BRCA1 gene, a tenth oligonucleotide for detecting an insertion of 12 nucleotides at nucleotide number 5396+40 in intron 20 of a BRCA1 gene sequence, wherein said tenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5396+40 of the BRCA1 gene, an eleventh oligonucleotide for detecting a deletion of one nucleotide at nucleotide number 5150 of a BRCA1 gene sequence, wherein said eleventh oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 5150 of the BRCA1 gene, a twelfth oligonucleotide for detecting an amino acid change from serine to a stop codon at codon 1262 of a BRCA1 gene sequence, wherein said twelfth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 3904 of the BRCA1 gene, a thirteenth oligonucleotide for detecting an amino acid change from tyrosine to stop at nucleotide number 903 of a BRCA1 gene sequence, wherein said thirteenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 903 of the BRCA1 gene, and a fourteenth oligonucleotide for detecting a detecting an amino acid change from threonine to proline at nucleotide number 4164 of a BRCA1 gene sequence, wherein said fourteenth oligonucleotide specifically hybridizes to a region encompassing the nucleotide number 4164 of the BRCA1 gene.

It is unclear from the complaint whether Myriad has not asserted these claims because Invitae's genetic diagnostic methods are substantially different from the other Defendants sued in other lawsuits, or if Myriad is changing its litigation strategies at least with regard to whether it can assert claims to oligonucleotide primers and probes.

Myriad and its co-plaintiffs demand a jury trial, and request judgment of patent infringement, a preliminary and permanent injunction, an accounting and damages, delivery for destruction of all "products" that infringe any of the asserted claims, a finding of willful infringement, and a request for attorneys' fees, enhanced damages, and costs of suit.

Invitae's lawsuit seeks a declaratory judgment that its genetic diagnostic tests do not infringe any of Myriad's asserted patents and (or) that these patents are invalid. In its General Allegations, Invitae asserts that it is a CLIA-certified lab "that offers customizable, clinically-relevant next-generation sequencing-based genetic testing services." Among those services are "state of the art" genetic sequencing and testing methodologies that provide "a single test for numerous genes of interest at less than the cost of most single gene tests" currently available. These tests encompass "over 200 human genes," including the human BRCA 1 and BRCA 2 as well as the MUTYH genes that are the subject of Myriad's patents. Importantly, like Quest in its declaratory judgment action, Invitae alleges that it "performs its sequencing using a very different approach" than the ways claimed in Myriad's asserted patents.

Invitae's complaint acknowledges Myriad's complaint filed in Utah, and the company asserts that it intends to file a motion to dismiss in that action. Invitae asserts that "Myriad's filing of the Utah Action, however, makes it inescapably clear that an actual and justiciable controversy has arisen and presently exists between the parties with respect to the validity and infringement by Invitae of the Myriad Patents," justifying Invitae's attempt to have the California court grant judgment of non-infringement and/or invalidity. Invitae claims that it does not use BRCA gene-specific primers, and thus that it does not infringe any of Myriad's claims reciting primer-based hybridization or sequencing methods. In addition, like other defendants, Invitae invokes the Supreme Court (and Federal Circuit) decisions in AMP v. Myriad and the Supreme Court's Mayo v. Prometheus decision for its invalidity contentions ("A vast portion of the landscape purportedly claimed by the Myriad Patents has been washed away in the wake of the Federal Circuit and Supreme Court’s decisions" in those cases, according to Invitae).

Invitae also demands a jury trial, a declaration of non-infringement and invalidity and a finding that this is an exceptional case entitling Invitae to attorneys' fees and costs.

For those keeping score, there are now five patent infringement lawsuits pending in the District of Utah, against Ambry Genetics, Gene-by-Gene, Quest, GeneDx, and Invitae, and three declaratory judgment actions by Quest, Invitae, and Counsyl, pending in various California district courts.

For additional information regarding this and other related topics, please see: